It is believed that compared to normal cells, cancer cells require higher iron levels in order to sustain fast proliferation rates. Cell walls in various tumor types are characterized by upregulated expression of the transferrin receptor (TfR), which is responsible for increased cellular uptake of the iron transport protein transferrin (Tf). As such, the use of small-molecule scavengers (e.g., chelators) that avidly sequester intracellular iron ions is emerging as a potential therapeutic avenue in cancer research. Iron chelation therapy has been employed commonly and successfully for decades in the clinical treatment of iron overload disorders associated with genetic conditions such as β-thalassemia and hemochromatosis. In the context of cancer chemotherapy, iron chelators such as desferrioxamine (DFO, Desferal®), a clinically approved drug for iron overload treatment, have shown promising antiproliferative activity.
In clinical trials, however, their applicability has been hampered by dose-limiting toxicity and adverse side effects. Chelators derived from bacterial siderophores (e.g., DFO) or other high-affinity scaffolds affect iron levels not only in cancer cells but also in normal tissue and blood plasma in a non-discriminatory fashion. Although suitable for patients battling iron overload, such chelators are not designed to target the higher iron demand of malignant cells in cancer patients presenting normal or low systemic iron levels.
New levels of molecular design are required for chelation-based therapeutics to evolve from their established roles in metal overload treatment. For instance, several pro-chelator approaches are under investigation for the development of multifunctional chelators as therapeutic agents for conditions associated with metal dyshomeostasis, such as neurodegenerative diseases and Wilson's disease.
Because the intracellular environment of tumor cells presents lower (more reducing) potentials when compared to blood plasma and neighboring normal tissue, redox directed chelation therapy could lead to preferential or selective depletion of iron in cancer cells and ultimately tumor-targeted therapeutic avenues.
Therefore, there is a need for pro-chelators that can be activated for iron coordination following a reduction event within cancer cells.